This invention relates to compositions and method for the treatment of arthritis and related autoimmune diseases.
A known feature of autoimmune diseases is the presence of immune complexes. Immune complexes help eliminate foreign bodies such as microorganisms. In patients with diseases associated with immune complexes, the formation of the immune complex can be a malfunction of the normal system whereby in some cases the antibody response is directed against native material (self-antigen). In other cases the immune response is directed against the foreign substance repeatedly introduced into the system.
In rheumatoid arthritis, for example, the chronic inflammation of the synovial membrane of affected joints, as well as many of the extra-articular manifestations of the disease, have been ascribed to immune complexes (either localized in the joint or circulating). The immune complexes in patients with rheumatoid arthritis consist of IgG homopolymer complexes [i.e. IgG-(IgG)n, self-associated] or heteropolymers [i.e. IgM-(IgG)n], thereby suggesting that the immunoglobulins are both the antigen and the antibody. In addition, complement components are frequently bound to these complexes. The IgG molecules found in the complexes are referred to as IgG-rheumatoid factor (IgG-RF) while the IgM molecules in the complexes are called IgM-rheumatoid factors (IgM-RF).
In rheumatoid arthritis it has long been postulated that auto-sensitization to IgG may play a pivotal role in the pathogenesis of the disease, and immune complexes are formed through the binding of the IgM, IgG, or IgA rheumatoid factors to the constant region domains of IgG molecules. The immunogenic site on IgG has been localized to the Fc moiety, but there is no evidence for amino acid changes in the Fc of this IgG. Data on the carbohydrate composition of IgG present in the intermediate complexes isolated from the serum of patients with rheumatoid arthritis invariably show an increased level of sialic acid (usually Fab-associated) as compared to normal serum IgG [Hymes and Mullinax, J. Biol. Chem. 254, 3148 (1979); and Hansson et al., Scand. J. Immunol. 13, 57 (1981)], and decreased content of Fc-associated galactose [Hymes and Mullinax, supra]. In one case, this sialic acid was shown to occur on light chains, and was crucial for IgG self-association, since its removal by neuraminidase treatment abolished complex formation [Hymes and Mullinax, supra]. In a recent study [Pekelharing et al , Ann. Rheum. Dis. 47, 91 (1988)] it was found that serum IgG from patients with rheumatoid arthritis had a lower carbohydrate content and therefore presumably lower Fab N-glycosylation, consistent with the sequestration into complexes of IgG enriched in Fab N-glycosylation. Together, these observations suggest that immune-complex formation in rheumatoid arthritis could involve both Fab N-glycosylation and agalactosyl structures in the Fc. The molecular mechanism whereby these two factors might contribute to IgG auto-antigenicity or self-association are not known, but a study of the crystal structure of Fc provides some insight into this. The crystal structure [Sutton and Phillips, Biochem. Soc. Trans. 11, 130 (1982)] clearly indicates that each N-linked oligosaccharide in the Fc can interact with the protein surface of the CH2 domain, principally via the (NeuNAc.alpha.2.fwdarw.6)Gal.beta..fwdarw.4 segment of the Man .alpha..fwdarw.6 arm. This is the principal non-covalent protein-oligosaccharide interaction in Fc, and serves to restrain the Fc oligosaccharides, and also to mask certain underlying Fc polypeptide determinants. It is therefore suggested that the change in the degree of occupancy of the Fc carbohydrate-binding site, secondary to decreased outer-arm galactosylation of Fc oligosaccharides, could lead to IgG self-association through one of the following mechanisms. First, through the insertion into this vacant site of an appropriate Fab-linked oligosaccharide from another IgG molecule. Second, through the interaction of the affected IgG with either naturally occurring or induced anti-GlcNAc antibodies. Third, through interaction of the affected IgG with antibodies induced against the peptide (or peptide-oligosaccharide) epitopes previously largely masked by the native oligosaccharide. Self-association of IgG could occur by any of these mechanisms. Further, occupation of the vacant oligosaccharide-binding site by other serum or synovial fluid glycoprotein or cartilage components can also be envisaged.
Additional background information concerning glycosylation patterns in serum IgG of rheumatoid arthritis patients can be had by reference to the following four recent publications:
Parekeh et al., "Association of Rheumatoid Arthritis and Primary Osteoarthritis with Changes in the Glycosylation Pattern of Total Serum IgG," Nature 316, 452-457 (1985).
Parekh et al., "Galactosylation of IgG Associated Oligosaccharides: Reduction in Patients with Adult and Juvenile Onset Rheumatoid Arthritis and Relation to Disease Activity," Lancet i, 966-969 (1988).
Parekh et al., "A Comparative Analysis of Disease-Associated Changes in the Galactosylation of Serum IgG," J. of Autoimmunity 2, 101-114 (1989).
Rademacher et al., "The Role of IgG Glycoforms in the Pathogenesis of Rheumatoid Arthritis," Springer Seminars in Immunopathology 10, 231-249 (1988).
A recent publication by Pearson and Jamnejad, ICSU Short Rep., 2 (Adv. Gene Technol.), 269-270 (1985), reported that when rheumatoid factor IgM is incubated with sialyl-N-acetyl-lactose as an additional step in a conventional ELISA test, there was less subsequent interaction with the normal antigen IgG. However, no data are given and the naming of the sugar compound is indefinite. The reported conclusions were that rheumatoid factor from some patients may be specifically blocked by the sialyl-N-acetyl-lactose and that the enzyme galactosyl transferase thus may be involved in the etiology of rheumatoid arthritis.
The known relationships between sialyloligo-saccharides and rheumatoid arthritis can be summarized as follows: N-acetylneuraminosyl oligosaccharides of great structural diversity are the major constituents of human milk. That these structures may be important comes from the studies of Witt et al. [Nutr. Metab. 23, 51-61, (1979)] who suggested that these oligosaccharides were not just storage forms of sialic acid but were absorbed and distributed to the tissues intact. Since these studies, it has also become evident that sialyloligosaccharides are important as bacterial anti-adhesions, preventing infection in the newborn.
The urinary excretion of sialyloligosaccharides is known to increase during pregnancy. Interestingly, there is a pregnancy dependence for the excretion of sialyl N-acetyl-lactosamine isomers in urine in contrast to sialyl lactose containing isomers in human milk. The blood serum levels have not been measured. Urinary sialyloligosaccharide excretion can be used as an indicator of disease activity in patients with rheumatoid arthritis [Rheumatol. Int. 1, 7-10, (1981); Eur. J. Clin. Invest. 8, 405-409 (1978)]. Both the urinary excretion of sialyl-lactose and sialyl-N-acetyllactosamine isomers are increased in the disease.
More recent studies have shown that sialyl lactose and sialyl-N-acetyllactosamine may be low-molecular weight acute phase reactants [Ann. of Rheum. Dis. 41, 268-271 (1982)]. In this comparative study rheumatoid arthritis (RA) patients, with active, aggressive RA had a significantly higher urinary sialyl lactose content, serum CRP and SAA levels than patients with mild disease. In SLE, while sialyl lactose excretion was elevated relative to controls, the excretion correlated neither with serum CRP nor with SAA. This suggests the specific control mechanisms operate for the synthesis of sialyloligosaccharides in RA and pregnancy.
Still more recently, sialyloligosaccharides containing inositol have been found in pregnancy urine [Carb. Res. 115, 221-229 (1983)]. EQU NeuNAc.alpha.2-3Gal.beta.1-1L-myo-inositol
Their excretion by non-pregnant individuals has not yet been reported.
Research into `factors` from the urine of pregnant women was initiated in the 1940's by Hench in his search for the pregnancy factor which causes the remission of arthritis in pregnant women [Mayo Clin. Proc. 24, 167-178, (1949)]. His fractionation of urine led to the eventual discovery of cortisone. Subsequent studies, however, showed that cortisone was not the elusive pregnancy `factor`, which still remains chemically undefined today.